Toxicology

Question 1

What is toxicology?

Answer 1

• Study of the adverse effects of chemicals

Question 2

Discuss methods of exposure to Toxins?

Answer 2

• Deliberate exposure of specifically designed toxins.
• Deliberate over-exposure to natural toxin or drug.
• Environmental exposure to chemicals.
• Unexpected adverse effect to a drug

Question 3

Discuss unwanted effects of drugs.

Answer 3

• Side effects: relatively minor and reversible when treatment ceases or after a short while.
• Adverse effects: More serious and May be life threatening.
• Drug interactions: Unwanted effects that occur in presence of other drugs.
• Contraindications: Conditions that may precipitate an unwanted effect

Question 4

What are acute toxicity studies?

Answer 4

• Administration of a single dose or multiple doses can be tested.
• Monitoring for 14 days.
• Outcome is determined: adverse effects, death.

Question 5

What is subacute toxicology?

Answer 5

• Repeated dosing used (Usually 3 or 4 dose levels used).
• 14 days treatment.
• Histopathology and clinical chemistry
• Used to estimate dose for subchronic studies

Question 6

What is subchronic toxicology?

Answer 6

• Studies up to 90 days.
• Three doses used based on previous studies: low dose = non toxic, high doses = toxic but <10% fatal.
• Multiple endpoints: clinical chemistry, pathology, histopathology.

Question 7

What are Chronic toxicology studies?

Answer 7

• Studies of 3 mo to 2 yrs duration.
• Gross and microscopic studies are performed on all animals.
• Chronic studies often used to study carcinogenicity.
• Necessary to have control untreated animals.

Question 8

What are toxicology end points?

Answer 8

• Necessary to define what a toxic effect is: Death, organ damage, illness.

Question 9

What is LD50?

Answer 9

• Lethal dose.
• Acute toxicity study where death is endpoint.
• Examples: Sucrose: 29.7 g/kg (rat, oral), Botulinum toxin: 1 ng/kg (human, iv estimate).

Question 10

What is NOAEL?

Answer 10

• Defined as the highest dose tested that does not cause a statistically significant toxic response.
• Includes pharmacologic response.
• Not necessarily a risk-free dose.

Question 11

What are the problems with NOAEL?

Answer 11

• Must be a tested dose (DR curve is ignored).
• Depends on the number of animals used.
• Depends on assay used.

Question 12

What is LOAEL?

Answer 12

• Lowest Observed Adverse Effect Level.
• Lowest dose tested that generates a statistically significant toxic effect.
• Includes pharmacological response.

Question 13

What are the problems with LOAEL?

Answer 13

• Must be a tested dose (DR curve is ignored).
• Depends on the number of animals used.
• Depends on assay used.

Question 14

What is carcinogenesis?

Answer 14

• Carcinogenesis is the uncontrolled replication of tissue cells with a monoclonal character, implying origin from a single cell mutation.

Question 15

Describe the principles of carcinogenesis?

Answer 15

1. Initiation: Mutation in key regulatory pathways
2. Promotion: Expansion of the initiated cell through signal transduction pathways and inhibition of apoptosis.
3. Progression: Conversion of an initiated cell to a malignant cell
4. A complete carcinogen has all three activities

Question 16

What are non toxic carcinogenics?

Answer 16

• Drugs that are carcinogenic but are not mutagenic e.g. benzene, saccharin.
• May be due to promotion of spontaneous initiated tumours.
• May cause direct toxicity, cell damage and cell proliferation enhancing carcinogenesis.

Question 17

What is developmental toxicology?

Answer 17

• Adverse effects that may arise from pre-conception through to puberty due to exposure to a drug.
• Teratology: defects that occur between conception and birth.
• Reproductive toxicology: adverse effects of exposure to a drug on either the male of female reproductive systems

Question 18

What is genotoxicity?

Answer 18

• Determines if there is a potential to cause genetic damage
• Standard 3-test battery: test for gene mutations in bacteria, in vitro test for chromosomal damage in mammalian cells, in vivo test for chromosomal damage to rat haematopoietic cells.

Question 19

What are specific toxicology tests?

Answer 19

• Behavioural (neurotoxicity)
• Immunotoxicity
• Skin toxicity

Question 20

What is behavioural toxicity?

Answer 20

1. Abuse potential: Reinforcing effects (self-administration), discriminative effects (drug discrimination), physical dependence (withdrawal).
2. Functional observational battery: Behavioural tests, allow onset, progression, duration, reversibility of neurotoxicity to be determined.
3. Studies of nature of neurotoxicity

Question 21

What is skin toxicity?

Answer 21

• Usually drug is administered intradermally (sometimes with Freund’s complete adjuvant).
• Subsequent challenge is with drug only.
• E.g. Draize and Guinea pig maximization test

Question 22

What is photo-toxicity?

Answer 22

• Drugs can make the skin hypersensitive to sunlight.
• May be immunological.

Question 23

What are immunological toxic reactions?

Answer 23

• When proteins are used as drugs they can be antigenic e.g. monoclonal antibodies leading to an immune reaction.
• Binding to proteins making them antigenic.
• Requires prior exposure and usually metabolism.

Question 23

What are immunological toxic reactions?

Answer 23

• When proteins are used as drugs they can be antigenic e.g. monoclonal antibodies leading to an immune reaction.
• Binding to proteins making them antigenic.
• E.g. penicillin.
• Requires prior exposure and usually metabolism.

Question 24

What are the immune reaction types?

Answer 24

• Immediate reactions: Occur with 1 hour, usually IgE mediated (allergy), can cause anaphylaxis
• Delayed reactions: Occur after days of treatment, not IgE-dependent.

Question 24

What are the immune reaction types?

Answer 24

• Immediate reactions: Occur with 1 hour, usually IgE mediated (allergy), can cause anaphylaxis
• Delayed reactions: Occur after days of treatment, not IgE-dependent.

Question 25

What cause immune thrombocytopenia?

Answer 25

• Heparin-induced thrombocytopenia
• Heparin binds to PF4 on platelets
• Antibody binds to platelets
• Antibody-bound platelets are cleared

Question 26

What is toxicogenetics?

Answer 26

• Gene polymorphisms can alter the response to a drug (pharmacogenetics).
• Can increase susceptibility to toxic effects.

Question 27

What is idiosyncratic toxicity?

Answer 27

• Not dose-dependent
• Probably due to genetic polymorphisms: Often in metabolising enzymes.
• Can also be due to immune response.
• Difficult to predict.